Formulations for the treatment and prevention of obesity

ABSTRACT

Disclosed are compositions containing:
         a)  Phaseolus vulgaris  extract;   b)  Cynara scolymus  extract;   c)  Echinacea angustifolia  extract;   d)  Vitis vinifera  extract   and optionally   e)  Panax ginseng  extract,   mixed with suitable excipients.

This U.S. non-provisional application is a divisional application ofU.S. application Ser. No. 14/433,179 filed on Apr. 2, 2015, which isU.S. national stage of PCT/EP2013/071138 filed on 10 Oct. 2013, whichclaims priority to and the benefit of Italian Application No.MI2012A001727 filed on 12 Oct. 2012, the contents of which are allincorporated herein by reference in their entireties.

The present invention relates to combinations of medicinal plantextracts useful in the prevention and treatment of obesity and excessweight.

PRIOR ART

Excess weight and obesity are rising to a worrying extent in all theindustrialised countries, and may affect up to 50% of the population inthe next decade. Obesity affects the health of the sufferer, withadverse effects on the cardiovascular, musculoskeletal andgastrointestinal systems.

Obesity is associated with a disorder of the lipid metabolism which, inturn, is influenced by a biochemical and hormonal profile involvingglucose, insulin resistance, dyslipidaemia and neurovegetativemediators.

The onset of a state of excess weight/obesity at a young age is a highlysignificant risk factor for the activation of processes which, at adultage, can promote metabolic syndrome, type 2 diabetes and the developmentof adult obesity. Many metabolic, cardiovascular and oncologicaldisorders seem to be closely related to insulin resistance and theproduction of inflammatory cytokines. It is therefore of primaryimportance to deal with obesity by effective means which, combined withdiet and lifestyle changes, support the body during the weight loss andmaintenance stages.

Specific inhibitors of some enzymatic systems involved in theetiopathogenesis of obesity have been identified, in particularpancreatic lipase inhibitors of microbial origin (Orlistat) andserotonin reuptake inhibitors such as rimonabant and sibutramine.However, the side effects of said medicaments are such that they canonly be used in serious cases and only by a small part of thepopulation, their use for the youngest patients being particularlyunsuitable.

WO2008107184 discloses compositions containing Cynara scolymus andPhaseolus vulgaris extracts for the treatment of obesity.

However, there is still a need for more effective alternative remedieswhich are easier to manage in the treatment of obesity.

DESCRIPTION OF THE INVENTION

It has now been found that a combination of medicinal plant extractscauses a reduction in body weight by burning the fats accumulated inreserve organs. The combination according to the invention comprisesextracts of Phaseolus vulgaris, Cynara scolymus, Vitis vinifera,Echinacea angustifolia and optionally, Panax ginseng.

The invention therefore relates to pharmaceutical or nutraceuticalcompositions comprising said extracts, for use in the prevention andtreatment of obesity and excess weight in general, and in young peoplein particular.

The compositions according to the invention contain α-glucosidase and/orα-amylase inhibitors, gastric and pancreatic lipase inhibitors,anti-free radical compounds, anti-inflammatories and compounds able toincrease energy expenditure. The compositions according to the inventiontherefore reduce the absorption and transport of the glucose and lipidspresent in the diet, and stimulate the energy metabolism.

In particular, Phaseolus vulgaris extract possesses inhibiting activityagainst α-amylase, an enzyme that demolishes starches, thus promotingglucose absorption. The extract modulates the appetite, as it increasesthe feeling of fullness due to the presence of phytohaemagglutinin whichbinds the brush border membranes of the intestinal cells, thusstimulating the release of cholecystokinin (CCK) and glucagon-likepeptides [Carai M. A M. Brit. J. of Nutr. 3;1-7, 2011].

Cynara scolymus extract has a high content of caffeoylquinic acids,which are known to inhibit the transport of glucose, and consequentlyits absorption in the gastrointestinal tract. Low glucose absorption isa crucial parameter to prevent the postprandial blood glucose peak.

Vitis vinifera seed extract has inhibiting properties againstα-glucosidase and pancreatic lipase. The modulation of said enzymes isan extremely important aspect in controlling obesity. In particular,inhibition of pancreatic lipases, enzymes that hydrolyse the lipids inthe intestinal tract and promote their absorption, is essential for thecontrol of obesity. Grape seeds extract inhibits lipoprotein lipase(LPL), which releases lipids into the plasma, thus helping to reducelipid absorption and improve the blood lipid profile. This activity issynergic with the anti-free radical activity typically present after ameal rich in fats, promoting the maintenance of a good state of theblood vessel endothelium and a consequent reduction of the risk ofcardiovascular and metabolic diseases [Moreno D. A., Nutrition, 19;876-879, 2003].

The lipophilic extract of Echinacea spp., preferably Echinaceaangustifolia, contains alkylamides with activity that inhibits therelease of pro-inflammatory cytokines (IL-6 and IL-8). Excessweight/obesity is often accompanied by a generalised inflammatory statewherein inflammatory cytokines contribute to significantly inducing thestate known as metabolic syndrome.

Echinacea alkylamides, due to their lipophilic nature and rapidabsorption, synergically enhance the anti-inflammatory activity of othercompounds contained in Cynara scolymus and Vitis vinifera extracts.

Panax ginseng (or Panax quinquefolium or other species containing thesame active substances) is a known “adaptogen”, namely a plant thatfavourably modifies many stress conditions in the body. Ginsenosides,considered to be the main active substances in the extract, inhibitpancreatic lipase by reducing the absorption of fats and improving theblood lipid profile. Ginsenosides are also inducers of particularproteins (UCP-2) which increase energy consumption with thermogenicactivity, inducers of the carnitine-palmitoyl-transferase enzyme, whichhas an antiadipogenic effect, and stimulate the synthesis ofneuropeptide Y antagonists with an anorexigenic effect.

Ginseng also stimulates protein synthesis in the liver, which canimprove the lipoprotein ratio in accumulation areas [Seung-Hwang K.,Pharm. Res., 48; 511-513, 2003].

Said extracts are known and available on the market. A Cynara scolymusextract is disclosed, for example, in WO 2007/006391, the preparation ofa Phaseolus vulgaris extract is disclosed in WO2007071334, thepreparation of Echinacea extracts is described in EP1539203, and thepreparation of Vitis vinifera extracts is disclosed in U.S. Pat. No.5,484,594.

Particularly preferred are Phaseolus vulgaris extract with an α-amylaseinhibitor content of 300 μg/mg and a lectin value of 10000 U/mg, aCynara scolymus extract with a caffeoylquinic acid content rangingbetween 20 and 70%, preferably 35%, and a Panax ginseng extract having aginsenoside content (determined by HPLC) of 7%.

The unit doses of the various extracts can vary within wide limits, inview of their high tolerability. In any event, the list below indicatesthe typical dose ranges that could be adapted according to the activeingredient content of the extracts, the particular form ofadministration and the therapeutic objective to be achieved (primingdose and maintenance dose, for example):

-   -   Phaseolus vulgaris: 50 to 200 mg, preferably 100 mg    -   Cynara scolymus: 50 to 200 mg;    -   Echinacea angustifolia: 10 to 50 mg;    -   Vitis vinifera: 100 to 250 mg;    -   Panax ginseng: 20 to 50 mg.

A particularly preferred composition contains:

-   -   100 mg of Phaseolus vulgaris extract with an α-amylase inhibitor        content of 300 μg/mg and a lectin value of 10000 U/mg.    -   40 mg of Panax ginseng extract with a ginsenoside content        (determined by HPLC) of 7%, and 50 to 200 mg, preferably 100 mg,        of a Cynara scolymus extract with a caffeoylquinic acid content        of 20 to 70%, preferably 35%;    -   25 mg of Echinacea angustifolia extract;    -   200 mg of Vitis vinifera pips.

The formulations will also contain conventional excipients, andoptionally lipophilic extracts of Foeniculum vulgare or Melissaofficinalis, which latter reduce the flatulence and spasms induced byexcess gas production.

The formulations will typically be administered once or a twice a day,preferably twice a day. If Panax ginseng is present, the product willpreferably be administered during the daytime to avoid adverse effectson sleep.

The compositions according to the invention, as well as reducing thepostprandial blood glucose level, also cause a surprising reduction inthe daily systemic blood glucose level. The resulting blood insulinlevel favourably influences the glycolipid metabolism, which is apre-requisite for controlling excess weight. The compositions accordingto the invention also cause an unexpected increase in HDL cholesterol inhyperlipaemic subjects and in those whose HDL cholesterol level is belownormal following treatment with cholesterol-lowering medicaments. Inparticular, a reduction of about 20% in total cholesterol and LDLcholesterol, and a significant increase of over 20% in HDL cholesterol,was observed. In a case study of patients with total cholesterol levelsranging from 220 to 280 mg/dl, said increase was constant over time, andappeared to be much more marked than reported for traditional herbalpreparations to date.

The compositions according to the invention act on the whole metabolicprofile of both children and adults, and are particularly suitable forthe treatment of obesity, excess weight, metabolic syndrome and type 2diabetes, especially in women.

The different activities of the constituents of the compositionsaccording to the invention, which modify the absorption of fats andcarbohydrates, the blood glucose and blood lipid levels, accumulation offats in the tissues, the feeling of fullness and psychological stimulus,combine to provide an effective solution to the therapeutic problem ofobesity, especially in young people.

Moreover, the protective activity of the extracts attenuates theoxidative and inflammatory processes which, in time, can cause permanentdamage to the circulatory apparatus. Finally, the formulations accordingto the invention have the advantage of acting synergically on a numberof factors without aggressive action on a single biological target, thusavoiding the major physical and neurological side effects that causemost failures of conventional treatments.

According to a preferred aspect, the compositions according to theinvention will be formulated as capsules, single-dose sachets,conventional or gastroprotected tablets, to promote topical localactivity while leaving the digestive function unchanged at stomachlevel.

According to a further aspect, the compositions according to theinvention may be administered together with other substances having auseful or complementary activity. In paediatric medicine, preferencewill be given to sachet formulations due to their ease ofadministration, while capsules or tablets will be used for adults andschool-age children.

The compositions according to the invention will be formulated accordingto conventional methods, such as those described in “Remington'sPharmaceutical Handbook”, Mack Publishing Co., N.Y., USA. In particular,the compositions according to the invention will be formulated byconventional plant ingredient formulation techniques, which requireparticular care to be taken to avoid interactions with the excipientsand the capsule matrices. Examples of oral formulations are tablets,dragées, soft and hard gelatin capsules, and cellulose capsules.

The examples set out below further illustrate the invention.

Example 1—Tablets

Extracts of:

Cynara scolymus (caffeoylquinic acid 30%) 200 mg Phaseolus vulgaris 100mg Panax ginseng 100 mg Echinacea angustifolia  25 mg Vitis vinifera 200mg Microcrystalline cellulose 310 mg Sodium croscarmellose  30 mgMagnesium stearate  8 mg Silica  8 mg

Example 2—Tablets

Extracts of:

Cynara scolymus (caffeoylquinic acid 30%) 200 mg Phaseolus vulgaris 100mg Echinacea angustifolia  25 mg Vitis vinifera 200 mg Microcrystallinecellulose 410 mg Sodium croscarmellose  30 mg Magnesium stearate  8 mgSilica  8 mg

Example 3

A non-randomised open-label clinical trial was conducted to evaluate theactivity of example 1 combined with example 2. The two tablets wereadministered at the main meals (1 with the midday meal and 2 with theevening meal) to a group of 10 young people (between 12 and 16 yearsold) using a Body Mass Index (BMI) of between 26 and 30 and absence ofconcomitant disorders as selection criteria.

5 groups were set up (group 1: 200 mg Cynara sc. and 100 mg Phaseolusvulg., group 2: 100 mg Panax Gin., group 3: 25 mg Echinacea ang., group4: 200 mg Vitis vinif., group 5: ex. 1 and ex. 2 as described above) andthe individual extracts were compared with the examples specified above,evaluating the blood cholesterol, blood triglycerides, blood glucose andBMI values before treatment and after 1 month's treatment.

TABLE 1 Mean value % variation in Mean value % variation in Mean value %variation in of total mean value of of LDL mean value of of HDL meanvalue of cholesterol total cholesterol cholesterol LDL cholesterolcholesterol HDL cholesterol before after 1 month's before after 1month's before after 1 month's Group treatment treatment treatmenttreatment treatment treatment Group 1 267 −4.5 172 −3.2 35 3.8 (10patients) Group 2 278 −4.1 188 −5.2 34 6.5 (20 patients) Group 3 271−6.2 181 −5.6 36 3.2 (19 patients Group 4 265 −0.5 175 −0.1 37 0.6 (23patients Group 5 275 −23 198 −20.88 33 22 (23 patients)

TABLE 2 % variation in Mean value % variation in Mean value mean valueof of blood mean value of % variation in of triglycerides triglyceridesglucose blood glucose Mean mean BMI value before after 1 month's beforeafter 1 month's BMI after one month's Group treatment treatmenttreatment treatment value treatment Group 1 285 −4.2 142 −11.2 28 −2.1(10 patients) Group 2 256 −8.0 131 −4.9 29 −1.2 (20 patients) Group 2273 −6.3 129 −1.6 27 −1.3 (20 patients Group 4 277 −1.2 134 1.3 27 0.5(23 patients Group 5 267 −41 130 −22.4 28 −8.5 (23 patients)

The data reported above clearly indicate a significant reduction in thepostprandial and fasting blood glucose levels and an improvement in thelipid and body weight profile (Body Mass Index) after one month'streatment. In all the treated subjects a reduction in appetite wasobserved, which is important in order to maintain the balance reached.

1. Compositions comprising: a) extract of Phaseolus vulgaris; b) extractof Cynara scolymus; c) extract of Echinacea angustifolia; d) extract ofVitis vinifera; and optionally e) extract of Panax ginseng; mixed withsuitable excipients.
 2. Compositions according to claim 1 in the form oftablets, dragées, soft or hard gelatin capsules or cellulose capsules.3. Compositions according to claim 1 wherein the extract of Phaseolusvulgaris has an α-amylase inhibitor content of 300 μg/mg and a lectinvalue of 10000 U/mg.
 4. Compositions according to claim 1 wherein theextract of Cynara scolymus has a caffeoylquinic acid content rangingbetween 20 and 70%, preferably 35%.
 5. Compositions according to claim 1wherein the extract of Panax ginseng has a ginsenoside content of 7%determined by HPLC.
 6. Compositions according to claim 1 containing 100mg of extract of Phaseolus vulgaris, 50 to 200 mg of an extract ofCynara scolymus, 25 mg of extract of Echinacea angustifolia and 200 mgof extract of Vitis vinifera pips.
 7. Compositions according to claim 6,also containing 40 mg of extract of Panax ginseng.